Cancer is one of the most widespread and dreaded diseases in the world today. It is feared largely because it is known to be difficult to cure, since, cancer results from the uncontrolled multiplication of imperceptibly modified normal human cells. Cancer claims maximum loss of human lives worldwide annually. Thus the fight against cancer still remains an open cause requiring determined pursuits (WHO fact sheet No 297, February 2015; Siegel, R. L.; Miller, K. D.; Jemal, A. C A. Cancer J. Clin., 2016, 66, 7-30).
Among several strategies invoked in battling the cancer, chemotherapy, involving targeting the cancer cells with transition metal complexes, remains a popular approach (Wani, W. A.; Baig, U.; Shreaz, S.; Shiekh, R. A.; Iqbal, P. F.; Jameel, E.; Ahmad, A.; MohdSetapar, S. H.; Mushtaqueh, M.; Hun. L. T. New. J. Chem., 2016, 40, 1063-1090; Liu. W.; Gust, R. Chem. Soc. Rev., 2013, 42, 755-773; Page, S. Educ. Chem., 2012, 49, 26-29). Thus, recent advances in medicinal inorganic chemistry give significant prospects for the utilization of metal complexes in the development of anticancer drugs (Baile M. B et. al.: International Journal of Pharma Research & Review, August 2015; 4(8):59-66).
Though numerous transition metal complexes are known to exhibit anticancer properties, the platinum (Pt) based blockbuster drug, Cisplatin inhibits cancer cell proliferation by binding to DNA inside the nucleus of a cancer cell. In 1960, the anti-tumor activity of an inorganic complex cis-diammine-dichloroplatinum (II) (Cisplatin) was discovered. Since then, Cisplatin has developed into becoming the most successful drug against carcinoma (Farrell, N. P.; Chem. Soc. Rev., 2015, 44, 8773-8785; Wheate, N. J.; Walker, S.; Craig, G. E.; Oun, R. Dalton Trans., 2010, 39, 8113-8127). Despite the popularity, Cisplatin suffers from limitations arising from its low solubility, leading to inconvenient intravenous administration of the drug, various toxicity issues and the gradual acquired resistance of the cancer cells against the drug, thus adding to the need for alternative metallodrugs for cancer therapy (Pabla, N.; Dong, Z. Kidney Int., 2008, 73, 994-1007; Rabik, C. A.; Dolan, M. E. Cancer Treat. Rev., 2007, 33, 9-23; Yao, X.; Panichpisal, K.; Kurtzman, N.; Nugent, K. Am. J. Med. Sci., 2007, 334, 115-124).
In view of the aforementioned disadvantages of using Pt based metallodrug Cisplatin, there is a need in the relevant art to develop other active metallodrugs, as anti-cancer actives. Ghosh, P. et. al.: J. Organomet. Chem. 2009, 694, 2328-2335 discloses the reduced toxicity of chelated nickel N-heterocyclic carbene complexes bearing potential utility as immunotolerance agents. Pd based N-heterocyclic carbene (in short “NHC”) metal complexes that are known in the art are as catalytically active ligands (Organ et. al.: Angew. Chem. Int. Ed. 2007, 46, 2768-2813; Nolan et. al: Organometallics 2004, 23, 3752-3755),
Recently, some Pd—NHC metal complexes have been designed and reported to have anti-cancer properties. Ghosh, P. et. al.: J. Am. Chem. Soc. 2007, 129, 15042-15053 discloses anticancer activities of the imidazole based Pd—NHC complexes; Haque et. al.: Metallomics, 2013, 5, 760-769 reveals chlorine (Cl)—Pd—NHC complex mimicking Pt-based NHC complexes like Cisplatin and its superior anti-cancer activity over Cisplatin; review article Kapdi et. al: Chem. Soc. Rev., 2014, 43, 4751-4777 reports that Cl—Pd—NHC, show anti-tumour activity against three human tumour cells namely cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116).
Selectivity towards the cancer cells as opposed to its normal counterparts is an important marker of a potent anticancer compound. In this regard, Che. C. M. et al, discloses less cytotoxicity of a cyclometalated palladium N-heterocyclic carbene complex toward the normal human fibroblast cell line (CCD-19Lu, IC50=11.8 μm) (Che. C. M. et al, Angew. Chem. 2016, 128, 12114-12118).
Lastly, the gradual acquired resistant towards anticancer drugs is an important issue to resolve for designing an effective drug. Thus, bearing all of the aforementioned issues of the selectivity, the mechanistic understanding and that of the gradual acquired resistant towards anticancer drugs, there is a long-standing requirement of having highly effective anticancer activities of such Pd—NHC compounds. Hence, there is still a need in the art to develop active Pd—NHC metal complexes with enhanced therapeutic anti-cancer potency in comparison to those reported in the above prior arts.
Accordingly, the present inventors have developed chiral compounds of a series of enantiomeric pairs of palladium N-heterocyclic carbene (Pd—NHC) complexes with high potency anti-cancer activities.